ABSTRACT Cystic fibrosis (CF), one of the most common genetic disorders, is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes a cAMP-activated chloride channel. Clinically, over 90% of CF patients die of lung bacterial infection. Despite great progress made in understanding the molecular defect of this disease, the central issue as to how the chloride channel defect leads to the host lung defense failure has not been solved. CF lung infections are surprisingly restricted to a narrow set of opportunistic pathogens, including Pseudomonas aeruginosa, Staphylococcus aureus and Haemophilus influenzae. It is unknown why CF lungs selectively permit the prevalence of these particular bacteria. In normal host lung defense, neutrophils and monocytes/macrophages are the two major lung- recruited immune cells utilized against lung bacterial infection. We previously discovered that CFTR dysfunction in CF neutrophils undermines their capacity to kill Pseudomonas aeruginosa. Research from other laboratories identified a similar defect in CF macrophages. However, whether these innate immune defects determine CF lung pathogen selection has not been investigated. We hypothesize that myeloid CFTR defect in lung-recruited immune cells disproportionately affects the killing of CF pathogens versus non-CF pathogens, giving the CF pathogens a survival advantage. To test this hypothesis, we put forward two specific aims for this R21 proposal: 1) to verify that CFTR loss-of-function in neutrophils and/or monocytes/macrophages affects lung bacterial clearance disproportionately in favor of CF pathogens; 2) to test that adoptive transfer of functional neutrophils or monocytes corrects the CF pathogen clearance defect differentially. Completion of this research will demonstrate the central role of CF innate immune cells in CF lung disease pathogenesis, which may reveal novel therapeutic targets for the development of effective therapies for CF, a devastating disease that affects 1/~3000 live births in the US.